Brimonidine gel compositions and methods of use

ABSTRACT

Improved topical gel compositions, such as those containing brimonidine, for the treatment of skin disorders are described. The gel compositions contain carbomer and methylparaben, and are substantially free of methylparaben crystalline particles after an extended period of storage.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.13/824,635, filed Jun. 21, 2013, which is a Section 371 of InternationalApplication No. PCT/EP2011/068263, filed Oct. 19, 2011, which waspublished in the English language on Apr. 26, 2012, under InternationalPublication No. WO 2012/052479 A2, which was a Non-Provisional of U.S.Provisional Patent Application No. 61/405,388 filed on Oct. 21, 2010,and also claims priority from French Application No. 1058612, filed Oct.21, 2010, the disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Parabens are esters of para-hydroxybenzoic acid. They are used primarilyfor their bactericidal and fungicidal properties. Examples of parabensinclude methylparaben, ethylparaben, propylparaben, butylparaben,isobutylparaben, isopropylparaben, benzylparaben and their salts.Because of their low costs, long history of safe use and the inefficacyof natural alternatives, parabens are widely used as preservatives inthe cosmetic and pharmaceutical industries. See Darbre et al., 24 J.Appl. Toxicol. 5-13 (2004) and references therein.

Carbomer is a generic name of Carbopol®, a trademarked product fromLubrizol. Carbomer and Carbopol® are used interchangeably in the presentapplication, referring to a synthetic polymer of acrylic acidcross-linked with polyalkenyl ethers or divinyl glycol. It can be ahomopolymer of acrylic acid, cross-linked with an allyl etherpentaerythritol, allyl ether of sucrose, or allyl ether of propylene.Carbomers have been used as vehicles for drug delivery. They have a longhistory of safe and effective use in topical gels, creams, lotions, andointments, as supported by extensive toxicology studies. They have beenshown to have extremely low irritancy properties and are non-sensitizingwith repeat usage. Carbomers or carbomer copolymers have been used intopical formulations, e.g., for thickening, emulsifying or suspending.

Brimonidine is a selective alpha-2-adrenergic agonist. It has been usedas either monotherapy or as adjunctive therapy to lower intraocularpressure (IOP) in the treatment of glaucoma and ocular hypertension(OHT) since its approval in 1996. Brimonidine has also been found to beuseful in treating various skin disorders, such as rosacea, erythemacaused by rosacea, see, e.g., U.S. Ser. No. 10/853,585 to DeJovin etal.; U.S. Ser. No. 10/626,037 to Scherer; U.S. Ser. No. 12/193,098 toTheobald et al.; telangiectasias, see, e.g., U.S. Patent ApplicationPublication No. 2006/0264515. Topical gel compositions comprisingbrimonidine, carbomer and paraben(s) for the treatment of skin disordershave been described, see for example, U.S. Ser. No. 10/853,585 toDeJovin et al.; U.S. Ser. No. 12/193,098 to Theobald et al., etc.

In the present invention, crystalline particles of methylparaben havebeen unexpectedly observed in some brimonidine topical gel formulationsand placebo formulations containing carbomer and methylparaben.

There is a need for a topical gel composition containing carbomer andmethylparaben that is substantially free of paraben crystallineparticles and meets the antimicrobial requirement over an extendedperiod of storage. Such compositions and related methods and productsare described in the present application.

BRIEF SUMMARY OF THE INVENTION

In one general aspect, embodiments of the present invention relate to atopical gel composition comprising:

-   -   0.05 to 0.20% (w/w) methylparaben;    -   one or more second preservatives;    -   0.80 to 1.50% (w/w) carbomer; and    -   9.0 to 13.0% (w/w) total polyol;    -   wherein the topical gel composition has a pH of 4.5 to 7.5; and    -   wherein when the concentration of methylparaben is greater than        0.15% (w/w), the concentration of carbomer is less than 1.25%        (w/w).

In another general aspect, embodiments of the present invention relateto a topical gel composition comprising:

-   -   0.01 to 5% (w/w) brimonidine;    -   0.05 to 0.20% (w/w) methylparaben;    -   one or more second preservatives;    -   0.80 to 1.50% (w/w) carbomer; and    -   9.0 to 13.0% (w/w) total polyol;    -   wherein the topical gel composition has a pH of 4.5 to 7.5; and    -   wherein when the concentration of methylparaben is greater than        0.15% (w/w), the concentration of carbomer is less than 1.25%        (w/w).

Another general aspect of the present invention relates to a topical gelcomposition comprising:

-   -   0.1 to 0.6% (w/w) brimonidine tartrate;    -   0.05 to 0.15% (w/w) methylparaben;    -   one or more second preservatives selected from the group        consisting of sodium benzoate, phenoxyethanol, benzyl alcohol,        imidazolidinyl urea, and diazolidinyl urea;    -   0.80 to 1.50% (w/w) carbomer;    -   4.5 to 6.5% (w/w) propylene glycol;    -   4.5 to 6.5% (w/w) glycerol; and    -   purified water;    -   wherein the pH of the topical gel composition is adjusted to a        pH of 5.0 to 6.5 by an adequate amount of sodium hydroxide        aqueous solution.

In another general aspect, embodiments of the present invention relateto a method of treating or preventing a skin disorder in a subject. Themethod comprises topically administering to a skin area of the subject atopical gel composition according to an embodiment of the presentinvention, wherein the skin area is, or is prone to be, affected by theskin disorder.

Other aspects, features and advantages of the invention will be apparentfrom the following disclosure, including the detailed description of theinvention and its preferred embodiments and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Various publications, articles and patents are cited or described in thebackground and throughout the specification; each of these references isherein incorporated by reference in its entirety. Discussion ofdocuments, acts, materials, devices, articles, or the like which havebeen included in the present specification is for the purpose ofproviding context for the present invention. Such discussion is not anadmission that any or all of these matters form part of the prior artwith respect to any inventions disclosed or claimed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention pertains. Otherwise, certain terms usedherein have the meanings as set forth in the specification. All patents,published patent applications and publications cited herein areincorporated by reference as if set forth fully herein. It must be notedthat as used herein and in the appended claims, the singular forms “a,”“an,” and “the” include plural references unless the context clearlydictates otherwise.

As used herein, “erythema or a symptom associated therewith” is intendedto encompass any type or classification of redness of skin caused byhyperemia or congestion of the capillaries in the lower layers of theskin, and any symptom associated therewith. The term “erythema or asymptom associated therewith” encompasses skin redness or rash resultingfrom any causes. For example, it can be caused by skin injury, surgeryand other procedures on the skin, infection, inflammation, emotion,exercise, heat (erythema ab igne), cold, photosensitivity, radiationtherapy, allergy, hot flush diseases, medications, etc. Examples of“erythema or a symptom associated therewith” include, but are notlimited to, photosensitivity, erythema multiforme, and erythema nodusum,and their associated symptoms. Photosensitivity is caused by a reactionto sunlight, which often occurs when some factors, such as an infectionor a medication, increase the sensitivity to ultraviolet radiation.However, photosensitivity can also occur without any increasedsensitivity to ultraviolet radiation. Erythema multiforme ischaracterized by raised spots or other lesions on the skin, which areusually caused by a reaction to medications, infections, or illness.Most erythema multiforme is associated with herpes simplex or mycoplasmainfections. Erythema nodosum is a form of erythema that is accompaniedby tender lumps, usually on the legs below the knees, and may be causedby certain medications or diseases.

In one particular embodiment of the present invention, the term“erythema or a symptom associated therewith” includes erythema ofrosacea, i.e., erythema or a symptom associated therewith in a patientwith rosacea. Rosacea is an inflammatory skin disorder that generallyaffects the cheeks, nose, chin, and forehead of a patient. The majorsymptom of rosacea is erythema, i.e., the abnormal redness of the skin.

The term “erythema or a symptom associated therewith” encompassesdifferent degrees or grades of erythema or a symptom associatedtherewith, from mild to severe.

In view of the present disclosure, a skin area that is affected byerythema or that is prone to be affected by erythema can be identifiedusing any diagnostic signs or means known in the art, and can be treatedby methods according to embodiments of the present invention.

As used herein, “telangiectasia or a symptom associated therewith”refers to a visible, permanent abnormal dilation of blood vessels, suchas arterioles and venules. A visible blood vessel is a blood vesselvisually discernable as a line to an observer without the aid ofmagnifying equipment (other than spectacles normally used by theobserver). In various aspects, a telangiectatic blood vessel can have adiameter of at least about 0.5 mm. Telangiectasias can be associatedwith numerous conditions, syndromes, diseases, and disorders. Forexample, a facial telangiectasia can be associated with age, sunexposure, and alcohol use. Other diseases, disorders, conditions, andsyndromes associated with telangiectasias include, in non-limitingexample, scleroderma, hereditary hemorrhagic telangiectasia (Olser-Rendusyndrome), ataxia-telangiectasia, spider angioma, cutis marmoratatelangiectasia congenita, Bloom syndrome, Klippel-Trenaunay-Webersyndrome, Sturge-Weber disease, xeroderma pigmentosa, nevus flammeus,generalized essential telangiectasias (GET), angioma serpiginosum,spider naevi, CREST syndrome, basal cell carcinoma, and unilateralnevoid telangiectasia.

In one particular embodiment of the present invention, the term“telangiectasia or a symptom associated therewith” includestelangiectasia associated with rosacea, i.e., telangiectasia or asymptom associated therewith in a patient with rosacea.

In another particular embodiment of the present invention, the term“telangiectasia or a symptom associated therewith” includessun-induced/photodamage telangiectasia.

The term “telangiectasia or a symptom associated therewith” encompassesdifferent degrees or grades of telangiectasia or symptoms associatedtherewith, from mild to severe.

In view of the present disclosure, a skin area that is affected bytelangiectasia or that is prone to be affected by telangiectasia can beidentified using any diagnostic signs or means known in the art, and canbe treated by methods according to embodiments of the present invention.

As used herein, the term “brimonidine” refers to the compound(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine havingthe structure of Formula (I):

and any pharmaceutically acceptable salt of the compound, such asbrimonidine tartrate.

The phrase “pharmaceutically acceptable salt(s),” as used herein, meansthose salts of a compound of interest that are safe and effective fortopical use in mammals and that possess the desired biological activity.Pharmaceutically acceptable salts include salts of acidic or basicgroups present in the specified compounds. Pharmaceutically acceptableacid addition salts include, but are not limited to, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate,tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compoundsused in the present invention can form pharmaceutically acceptable saltswith various amino acids. Suitable base salts include, but are notlimited to, aluminum, calcium, lithium, magnesium, potassium, sodium,zinc, and diethanolamine salts. For a review on pharmaceuticallyacceptable salts see Berge et al., 66 J. Pharm. Sci. 1-19 (1977),incorporated herein by reference.

As used herein, the term “hydrate” means a compound of interest, or apharmaceutically acceptable salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound to it bynon-covalent intermolecular forces.

The term “topical gel composition” or “topical gel formulation,” as usedherein, means any gel formulation or composition which ispharmaceutically and/or cosmetically acceptable for topical delivery ofthe specified compound(s) according to embodiments of the invention.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredient in the specified amount, aswell as any product which results, directly or indirectly, fromcombinations of the specified ingredient in the specified amount.

As used herein, the term “subject” means any animal, preferably amammal, most preferably a human, to whom will be or has beenadministered compounds or topical formulations according to embodimentsof the invention. The term “mammal” as used herein, encompasses anymammal. Examples of mammals include, but are not limited to, cows,horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs,monkeys, humans, etc., more preferably a human. Preferably, a subject isin need of, or has been the object of observation or experiment of,treatment or prevention of a skin disorder, such as rosacea, erythema ofrosacea, telangiectasia, psoriasis, purpura, erythema of acne, eczema,non-rosacea-related inflammation of the skin, flushing, skin sagging,creasing and/or wrinkling, or a symptom associated therewith.

In one embodiment, “treatment” or “treating” refers to an amelioration,prophylaxis, or reversal of a disease or disorder, or of at least onediscernible symptom thereof. In another embodiment, “treatment” or“treating” refers to an amelioration, prophylaxis, or reversal of atleast one measurable physical parameter related to the disease ordisorder being treated, not necessarily discernible in or by the mammal.In yet another embodiment, “treatment” or “treating” refers toinhibiting or slowing the progression of a disease or disorder, eitherphysically, e.g., stabilization of a discernible symptom,physiologically, e.g., stabilization of a physical parameter, or both.In yet another embodiment, “treatment” or “treating” refers to delayingthe onset of a disease or disorder.

In certain embodiments, compounds of interest are administered as apreventative measure. As used herein, “prevention” or “preventing”refers to a reduction of the risk of acquiring a given disease ordisorder. In a preferred mode of the embodiment, the specified compoundsare administered as a preventative measure to a subject having apredisposition to a disease or disorder even though symptoms of thedisease or disorder are absent or minimal.

In an embodiment of the present invention, methylparaben crystallineparticles have been observed in brimonidine topical gel formulationscontaining 0.2% (w/w) or more methylparaben, particularly in batch sizesof 300 g to 250 kg. See Example 1 below. This observation is surprisingin view of the solubility of methylparaben. According to a MaterialSafety Data Sheet (MSDS) of methylparaben, the solubility ofmethylparaben in water is about 0.25% (w/w) at 20° C. or about 0.30%(w/w) at 25° C. The solubility of methylparaben in propylene glycol is 1in 5 at 25° C., the solubility of methylparaben in warm glycerol isabout 1.4%, and see: MSDS, Chemicals & Laboratory Equipment, ScienceLab.com, World Wide Web: sciencelab.com/msds.php?msdsId=9926083.Further, according to Handbook of Pharmaceutical Excipients (supra), thesolubility of methylparaben in propylene glycol is 1 in 5 at 25° C.,

In view of methylparaben's solubility in polyols and water, it wouldhave been reasonably expected that 0.30% (w/w) or less methylparabenwould remain completely soluble in a topical gel composition comprisingabout 4.5 to 6.5% (w/w) of a first polyol in which methylparaben issubstantially soluble, about 4.5 to 6.5% (w/w) of a second polyol, andabout 90% (w/w) or less water. The detection of methylparabencrystalline particles in the composition is completely unexpected. Notwishing to be bound by theory, the methylparaben crystalline particlesobserved in the brimonidine topical gel and placebo compositions mayhave been caused by one or more reasons, such as recrystallization ofmethylparaben during the manufacturing process, or recrystallization ofmethylparaben during storage resulting from excipient-excipientinteraction. Without the surprising observation made in the presentinvention, one would not have reasonably expected the existence ofmethylparaben crystals in the topical gel compositions, let alone todevelop an improved topical gel formulation free of the crystals.

Embodiments of the present invention relate to an improved topical gelcomposition that is substantially free of crystalline particles and hasmicrobiological quality over an extended period of storage. The improvedtopical gel composition according to an embodiment of the presentinvention comprises:

-   -   0.05 to 0.20% (w/w) methylparaben;    -   one or more second preservatives;    -   0.80 to 1.50% (w/w) carbomer; and    -   9.0% to 13.0% (w/w) total polyol;    -   wherein the topical gel composition has a pH of 4.5 to 7.5; and    -   wherein when the concentration of methylparaben is greater than        0.15% (w/w), the concentration of carbomer is less than 1.25%        (w/w).

According to embodiments of the present invention, the amount ofmethylparaben in the composition is about 0.05%, 0.075%, 0.10%, 0.125%,0.15%, or 0.20% (w/w).

Suitable second preservatives that can be used in embodiments of thepresent invention include any preservatives that are suitable fortopical application. Examples of the second preservatives include, butare not limited to, sodium benzoate, phenoxyethanol, benzyl alcohol,imidazolidinyl urea, or diazolidinyl urea. Additional examples of thesecond preservatives may include, quaternary ammonium compounds, such asbenzalkonium chloride, benzethonium chloride, cetrimide, dequaliniumchloride, and cetylpyridinium chloride; alcoholic agents, such as,chlorobutanol; antibacterial esters, such as esters ofparahydroxybenzoic acid; and other anti-microbial agents such aschiorhexidine, chlorocresol, benzoic acid, polymyxin, mupirocin,erythromycin, clindamycin, gentamicin, polymyxin, bacitracin, silversulfadiazine, etc.

Preferably, the second preservative is effective in inactivatingchallenge doses of Gram-negative and Gram-positive microorganisms, aswell as yeast.

According to embodiments of the present invention, the one or moresecond preservatives comprise phenoxyethanol and the amount ofphenoxyethanol in the composition is, or is greater than 0.3%, 0.35%,0.4%, 0.45%, or 0.5% (w/w).

According to embodiments of the present invention, the carbomer is asynthetic polymer of acrylic acid cross-linked with polyalkenyl ethersor divinyl glycol. It can be a homopolymer of acrylic acid, cross-linkedwith an allyl ether pentaerythritol, allyl ether of sucrose, or allylether of propylene. Examples of carbomers that can be used in thepresent invention include, but are not limited to, carbomer 910, 934P,940, 941, 1342, Carbopol® 974P (carbomer 974P), and Carbopol® 980(carbomer 980).

Preferably, the carbomer is carbomer 934P, carbomer 974P, or carbomer980.

According to embodiments of the present invention, the amount of thecarbomer in the composition is about 0.8%, 0.85%, 0.95%, 1.05%, 1.15%,1.25%, 1.35%, 1.45%, or 1.5% (w/w).

Polyol gel formulations with various ingredients solubilized thereinhave been used to minimize irritation when applied to the skin of asubject, while ensuring bioavailability of the active agent in theformulation. See Other III et al., “Gels and Jellies,” pp. 1327-1344 ofEncyclopedia of Pharmaceutical Technology, vol. 3 (ed. by Swarbrick etal., pub. by Marcel Dekker, Inc., 2002); or Pena, “Gel Dosage Forms:Theory, Formulation, and Processing,” pp. 381-388 of Topical DrugDelivery Formulations, (ed. by Osborne et al., pub. by Marcel Dekker,Inc., 1990). Polyols in gel formulations can serve one or morefunctions, such as solubilizing agents, moisturizers, emollients, skinhumectant, skin-penetration agents, etc. Suitable polyols that can beused in embodiments of the present invention include, but are notlimited to, glycerine, propylene glycol, dipropylene glycol, hexyleneglycol, butylene glycol, and liquid polyethylene glycols, such aspolyethylene glycol 200 to 600, and glycerol.

According to embodiments of the present invention, the amount of thetotal polyols in the composition is about 9.0% to 13.0% (w/w), forexample about 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, or13.0% (w/w).

In an embodiment of the present invention, the topical gel compositioncomprises at least a first polyol in which the methylparaben issubstantially soluble.

Preferably, the topical gel composition comprises the first polyol and asecond polyol, such as propylene glycol and glycerine, respectively.

According to embodiments of the present invention, the amount of each ofthe first and second polyols in the composition is independently about4.5% to 6.5% (w/w), for example 4.5%, 5.0%, 5.5%, 6.0%, or 6.5% (w/w).

In a preferred embodiment, a topical gel composition according toembodiments of the invention further comprises a water dispersible formof titanium dioxide (TiO₂), preferably at an amount that is sufficientto mask the color of brimonidine or another colored ingredient in theformulation, but would not cause irritation to the skin. TiO₂ may causemild irritation and reddening to the eyes, thus eye contact with theTiO₂-containing topically administrable composition should be avoided.Titanium dioxide imparts a whiteness to the topically administrablecomposition and helps to increase the opacity and reduce thetransparency of the composition. Titanium dioxide absorbs, reflects, orscatters light (including ultraviolet radiation in light), which canhelp protect products from deterioration. Titanium dioxide can also beused as a sunscreen to protect the user from the harmful effects ofultraviolet radiation that is part of sunlight.

According to embodiments of the present invention, the amount of waterdispersible form of titanium dioxide in the composition is about 0.04%,0.0425%, 0.0525%, 0.0625%, 0.0725%, or 0.08% (w/w).

In another general aspect, a topical gel formulation according to anembodiment of the present invention further comprises an activepharmaceutical ingredient, such as an alpha adrenergic receptor agonistor a pharmaceutically acceptable salt thereof, that is effective toprevent or treat a skin disorder.

Alpha adrenergic receptor agonists are well known in the art. In apreferred embodiment, the alpha adrenergic receptor agonist may be analpha-1 or alpha-2 adrenergic receptor agonist. The alpha adrenergicreceptor agonists included in the invention may or may not showselectivity for either the alpha-1 or alpha-2 adrenergic receptors. Forexample, some may be considered as being both alpha-1 and alpha-2adrenergic receptor agonists. More preferably, the alpha adrenergicreceptor agonist may be a selective alpha-1 or a selective alpha-2adrenergic receptor agonist.

Examples of selective alpha-1 adrenergic receptor agonists includeoxymetazoline, phenylephrine, and methoxyamine. Examples of selectivealpha-2 adrenergic receptor agonists include brimonidine,tetrahydrozoline, naphazoline, xylometazoline, epinephrine, andnorepinephrine.

In an embodiment of the present invention, the active pharmaceuticalingredient comprises 0.01 to 5% (w/w) brimonidine. The activepharmaceutical ingredient can optionally include one or morepharmaceutically active ingredients in addition to brimonidine,including, but not limited to, medications used to treat the skindisorder or the underlying disease that causes the skin disorder,antihistamines to control itching, antibiotics, corticosteroids,intravenous immunoglobulins, acetaminophen, etc.

In a preferred embodiment, the brimonidine is brimonidine tartrate.

According to embodiments of the present invention, the amount ofbrimonidine in the topical gel composition is about 0.05% to 0.1%, 0.1%to 0.4%, 0.4% to 0.7%, 0.7% to 1%, 1% to 2%, 2% to 3%, 3% to 4%, or 4%to 5% (w/w). Preferably, the amount of brimonidine tartrate in thecomposition is about 0.1 to 0.6% (w/w).

In a preferred embodiment of the present invention, a topical gelcomposition comprises:

-   -   0.1 to 0.6% (w/w) brimonidine tartrate;    -   0.05 to 0.15% (w/w) methylparaben;    -   one or more second preservatives selected from the group        consisting of sodium benzoate, phenoxyethanol, benzyl alcohol,        imidazolidinyl urea, and diazolidinyl urea;    -   0.80 to 1.50% (w/w) carbomer;    -   4.5 to 6.5% (w/w) propylene glycol;    -   4.5 to 6.5% (w/w) glycerol; and    -   purified water;    -   wherein the pH of the topical gel composition is adjusted to 5.0        to 6.5 by an adequate amount of sodium hydroxide aqueous        solution.

According to an embodiment of the present invention, the topical gelcomposition comprises greater than 0.3% (w/w) phenoxyethanol as thesecond preservative when 0.15% (w/w) or less methylparaben is used inthe formulation.

A topical gel composition according to embodiments of the presentinvention can comprise additional pharmaceutically acceptableexcipients, such as those listed in Remington: The Science and Practiceof Pharmacy, 866-885 (Alfonso R. Gennaro ed., 19th ed., 1995); Ghosh, T.K. et al., Transdermal and Topical Drug Delivery Systems (1997), herebyincorporated herein by reference. Examples of the additional excipientsinclude, but are not limited to, protectives, adsorbents, antioxidants,local anesthetics, buffering agents, surfactants, flavorants,fragrances, dyes, etc.

Suitable protective agents and/or cosmetic agents, and adsorbents caninclude, but are not limited to, dusting powders, zinc stearate,collodion, dimethicone, silicones, zinc carbonate, aloe vera gel andother aloe products, vitamin E oil, allantoin, petrolatum, titaniumdioxide, and zinc oxide.

Suitable antioxidants can include, but are not limited to, ascorbic acidand its esters, sodium bisulfite, butylated hydroxytoluene, butylatedhydroxyanisole, tocopherols, and chelating agents like EDTA and citricacid.

Suitable buffering agents can include, but are not limited to, acetatebuffers, citrate buffers, phosphate buffers, lactic acid buffers, sodiumbuffer, and borate buffers.

A topical gel composition according to embodiments of the presentinvention can further include local anesthetics and analgesics, such ascamphor, menthol, lidocaine, dibucaine, and pramoxine; antifungals, suchas ciclopirox, chloroxylenol, triacetin, sulconazole, nystatin,undecylenic acid, tolnaftate, miconazole, clotrimazole, oxiconazole,griseofulvin, econazole, ketoconozole, and amphotericin B.

A topical gel composition according to embodiments of the presentinvention can further include one or more antiseptics, such as iodine,povidine-iodine, benzalkonium chloride, benzoic acid, nitrofurazine,benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol,resorcinol, and cetylpyridinium chloride.

The topical gel composition according to embodiments of the presentinvention can be prepared by mixing the ingredients of the compositionaccording to known methods in the art, for example methods provided bystandard reference texts such as: Remington: The Science and Practice ofPharmacy, 1577-1591, 1672-1673, 866-885 (Alfonso R. Gennaro ed., 19thed., 1995); Ghosh, T. K. et al., Transdermal And Topical Drug DeliverySystems (1997), both of which are hereby incorporated herein byreference.

The pH of the topical gel formulations of the invention are preferablywithin a physiologically acceptable pH range, e.g., within the range ofabout 4.5 to about 7.5, more preferably, of about 5.0 to about 6.5, suchas a pH of about 5.1, 5.15, 5.2, 5.25, 5.3, 5.35, 5.4, 5.45, 5.5, 5.55,5.6, 5.65, 5.7, 5.75, 5.8, 5.85, 5.9, 5.95, 6.1, 6.15, 6.2, 6.25, 6.3,6.35, 6.4, 6.45, or 6.5. To stabilize the pH, preferably, an effectiveamount of a buffer is included. Acids or bases can be used to adjust thepH as needed.

In one general aspect, embodiments of the present invention relate to amethod of treating or preventing a skin disorder, such as rosacea,erythema of rosacea, telangiectasia, psoriasis, purpura, erythema ofacne, eczema, non-rosacea-related inflammation of the skin, flushing,skin sagging, creasing and/or wrinkling, or a symptom associatedtherewith, in a subject by topically administering to a skin area of thesubject a topical gel composition according to an embodiment of thepresent invention, wherein the skin area is, or is prone to be, affectedby the skin disorder. The relevant disclosures, e.g., on usingbrimonidine to treat the one or more of skin disorders, in U.S. Ser. No.10/853,585 to DeJovin et al.; U.S. Ser. No. 10/626,037 to Scherer; U.S.Ser. No. 10/607,439 to Gil et al.; U.S. Ser. No. 10/763,807 to Shanleret al.; U.S. Ser. No. 12/193,098 to Theobald et al.; U.S. PatentApplication Publication No. 2006/0264515 to DeJovin et al.; U.S. Ser.No. 12/621,942 to DeJovin et al.; U.S. Patent Application PublicationNo. 2005/0020600 to Scherer; and U.S. Patent Application Publication No.2009/0130027 to Shanler et al., are herein incorporated by reference asif set forth fully herein.

In an embodiment of the present invention, the topically administrablecomposition comprises about 0.1% to 0.6% (w/w), such as about 0.1%,about 0.15%, about 0.18%, about 0.2%, about 0.25%, about 0.3%, about0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, or about 0.6%by weight of brimonidine tartrate.

To treat or prevent a skin disorder, in view of the present disclosure,the topical gel compositions of the invention can be topically applieddirectly to the affected area in any conventional manner known in theart, e.g. by dropper, applicator stick, or cotton swab, as a mist via anaerosol applicator, via an intradermal or transdermal patch, or bysimply spreading a formulation of the invention onto the affected areawith fingers, a sponge, a pad, or wipes. Generally, the amount of atopical formulation of the invention applied to the affected skin arearanges from about 0.0001 g/cm² of skin surface area to about 0.05 g/cm²,preferably 0.002 g/cm² to about 0.005 g/cm² of skin surface area.Typically, one to four applications per day are recommended during theterm of treatment.

Methods of the present invention can be used in conjunction with one ormore other treatments and medications for the skin disorder, such as themedications used to treat the underlying disease that causes the skindisorder, antihistamines to control itching, antibiotics,corticosteroids, intravenous immunoglobulins, acetaminophen, etc.

The other medicament or treatment can be administered to the subjectsimultaneously with, or in a sequence and within a time interval of, theadministration of brimonidine, such that the active ingredients oragents can act together to treat or prevent the skin disorder. Forexample, the other medicament or treatment and brimonidine can beadministered in the same or separate formulations at the same ordifferent times.

Any suitable route of administration can be employed to deliver theadditional treatment or medication including, but not limited to, oral,intraoral, rectal, parenteral, topical, epicutaneous, transdermal,subcutaneous, intramuscular, intranasal, sublingual, buccal, intradural,intraocular, intrarespiratory, or nasal inhalation.

This invention will be better understood by reference to thenon-limiting examples that follow, but those skilled in the art willreadily appreciate that the examples are only illustrative of theinvention as described more fully in the claims which follow thereafter.

EXAMPLE 1 Observation of Methylparaben Crystalline Particles in TopicalGel Compositions

Crystalline particles were first observed visually in a sampling of 7tubes of a batch of brimonidine topical gel composition. These particleswere isolated. The identity of the particles was analyzed by severalanalytical methods, such as HPLC test for identification by comparisonof the retention time against standards, differential scanningcalorimetry (DSC) for determination of melting point, NMR for astructural identification (by 1H and 13C), mass/mass with UV detectorand QTOF to separate and identify the different masses, etc. Based onthese analyses, it has been concluded that the observed crystals arecrystals of methylparaben (hereinafter abbreviated as POBM or MPOB),which is a preservative used in the composition. According to theprocess used for manufacturing the batch, methylparaben was firstdissolved in propylene glycol at 50° C. (122-140° F.) in thepreservative phase.

Microscopic observations were performed on additional representativebatches of brimonidine topical gel compositions and placebo gelcompositions containing 1.25% (w/w) carbomer, POBM and otheringredients. The observations have been done on one tube of each batch,with the microscope Axiolab DRBKT Zeiss no. 023733.01 with a camera ICCZeiss or the microscope Olympus BX60. The microscopic observations weredone at 5° C. and room temperature.

As shown in Table 1, methylparaben crystalline particles wereunpredictably observed in both brimonidine and placebo gel compositionscontaining 0.2% or 0.3% by weight methylparaben (POBM).

TABLE 1 Results of microscopic observations of representative batches ofgel composition Date of Microscopic No. Tubes Date of ManufacturingComposition Observation Batch Size Observed Observation April 2008Placebo, 0.3% POBM Crystals 130 kg 7 December 2008 April 2008 Placebo,0.3% POBM No crystal 130 kg 5 December 2008 Jul. 1, 2009 Placebo, 0.3%POBM Crystals 300 g-2 kg 1 October 2009 Aug. 25, 2009 Placebo, 0.3% POBMCrystals 300 g-2 kg 1 October 2009 0.03% Brimonidine 200-250 kg Sep. 2,2009 0.3% POBM No crystal 1 February 2010 0.06% Brimonidine 200-250 kgSep. 7, 2009 0.3% POBM Crystals 1 February 2010 0.07% Brimonidine200-250 kg Jul. 6, 2009 0.3% POBM Crystals 1 February 2010 0.18%Brimonidine 300 g-2 kg Sep. 15, 2009 0.3% POBM Crystals 1 October 20090.5% Brimonidine 200-250 kg Jul. 16, 2009 0.3% POBM Crystals 1 February2010 1% Brimonidine 1% 200-250 kg Sep. 18, 2009 0.3% POBM No crystal 1February 2010 2% Brimonidine 2% 200-250 kg Sep. 29, 2009 0.3% POBM Nocrystal 1 February 2010 0.06% Brimonidine 300 g-2 kg Sep. 10, 2009 0.3%POBM Crystals 1 October 2009 1% Brimonidine 300 g-2 kg Sep. 17, 20090.3% POBM No crystal 1 October 2009 Jan. 12, 2010 Placebo, 0.2% POBMCrystals 300 g 1 Feb. 4, 2010 0.18% Brimonidine 800 g Dec. 22, 2009 0.2%POBM No crystal 1 Feb. 10, 2010

Assays were conducted to estimate the concentration of methylparabensolubilized in a batch originally containing 0.3% (w/w) ofmethylparaben, in which crystalline particles were observed.Centrifugation was performed on the batch to collect crystals at thebottom of the centrifuge tube, thus removing them from the supernatant.The methylparaben concentration in the supernatant was measured andfound to be about 0.2% (w/w), which was about 66% of the 0.3% (w/w) inthe original formulation. The reduction in the concentration of solublemethylparaben in the composition raises non-conformity issues and mayresult in poor microbiological quality of the composition over anextended period of storage.

The presence of methylparaben crystalline particles in the topical gelformulations is surprising in view of the solubility of methylparaben.In order to find a solution to avoid the crystallization problem,several hypotheses have been postulated and evaluated to uncover thepotential cause and possible solution of the problem.

EXAMPLE 2 Improved Topical Gel Compositions Free of MethylparabenCrystalline Particles

Various changes to the formulation and the process of manufacturing theformulation have been made in order to obtain improved topical gelformulations that are free of the observed paraben crystals and haveacceptable microbiological quality. For example, methylparaben, alsonamed methyl parahydroxybenzoate (POBM), was replaced with the morewater soluble Na POBM, but crystalline particles of Na POBM were stillobserved at 0.3% (w/w) Na POBM. Addition of 0.1% of EDTA into theformulation resulted in immediate recrystallization of the POBM at 0.3%(w/w) in the formulation, suggesting that the 0.3% (w/w) concentrationof POBM may be too high.

Numerous formulations with different ingredients and varyingconcentrations of the ingredients were made and tested for the presenceof the paraben crystals by microscopic observations. The microbiologicalquality of the formulations was also analyzed by using acceptance-testcriteria in preservative-efficacy testing (PET) in the United StatesPharmacopeia (USP) and the European Pharmacopoeia (EP).

Based on microscopic observations and PET analyses, it was found thatimproved topical gel compositions containing 0.05% to 0.20% (w/w)methylparaben; one or more second preservatives, such as 0.3% (w/w) ormore phenoxyethanol; 0.80 to 1.50% (w/w) carbomer, such as Carbopol®974PNF; 9.0% to 13.0% (w/w) total polyol, such as 4.5 to 6.5% (w/w) of afirst polyol, e.g., propylene glycol, 4.5 to 6.5% (w/w) of a secondpolyol, e.g., glycerol; and one or more other ingredients, such aspurified water, titanium dioxide, optionally an effective amount ofbrimonidine tartrate, with a pH of 5.0 to 6.5 adjusted by an adequateamount of sodium hydroxide, were free of methylparaben crystals after anextended period of storage and passed criteria of EP and USP. See Table2, in which the concentration of carbomer in each of the formulationswas 1.25% (w/w).

TABLE 2 Results of microscopic observations and PET of topical gelformulations Batch Period of Size Preservative Storage Microscopic (kg)Concentration (w/w) (weeks) Observation PET Result 2 0.1% MPOB 21 Nocrystal Failed criteria 0.3% Phenoxyethanol A of EP at 48 hours 200 0.1%MPOB 24 No crystal Passed EP and 0.4% Phenoxyethanol USP 2 0.125% MPOB12 No crystal Passed EP and 0.4% Phenoxyethanol USP 200 0,125% MPOB 7 Nocrystal Passed EP and 0.4% Phenoxyethanol USP

It was further discovered that when the amount of methylparaben was morethan 0.15% (w/w), decreasing the amount of carbomer reduced theformation of methylparaben crystals. See, for example, Table 3.

TABLE 3 Results of microscopic observation of gel compositions BatchMicroscopic Size Composition Observation 300G POBM: 0.2 Crystals afterone Phenoxyethanol: 0.3 month storage at RT Carbopol ® 980: 1.25 300GPOBM: 0.2 No crystal observed Phenoxyethanol: 0.3 after one monthCarbopol ® 980: 0.8 storage at RT

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

The invention claimed is:
 1. A topical gel composition, comprising:0.05% to 5% (w/w) brimonidine or brimonidine tartrate; 0.1% to 0.20%(w/w) methylparaben; 0.3% to 0.4% (w/w) phenoxyethanol; 0.80% to 1.50%(w/w) carbomer; 9.0% to 13.0% (w/w) total polyol, wherein the topicalgel composition has a pH of 4.5 to 7.5, and wherein when theconcentration of methylparaben is greater than 0.15% (w/w), theconcentration of carbomer is less than 1.25% (w/w).
 2. The topical gelcomposition of claim 1, wherein the total polyol comprises about 4.5% to6.5% (w/w) a first polyol, and one or more additional polyols.
 3. Thetopical gel composition of claim 1, wherein the carbomer is selectedfrom the group consisting of carbomer 934P, carbomer 974P, and carbomer980.
 4. The topical gel composition of claim 1, comprising: 0.1% to 0.6%(w/w) brimonidine tartrate; 0.1% to 0.15% (w/w) methylparaben; 0.3% to0.4% (w/w) phenoxyethanol; 0.80% to 1.50% (w/w) carbomer; 4.5% to 6.5%(w/w) propylene glycol; 4.5% to 6.5% (w/w) glycerol; and purified waterwherein the pH of the topical gel composition is adjusted to 5.0 to 6.5by an adequate amount of sodium hydroxide aqueous solution.
 5. Thetopical gel composition of claim 4, comprising greater than 0.3% (w/w)phenoxyethanol.
 6. The topical gel composition of claim 5, furthercomprising 0.04% to 0.08% (w/w) water dispersible form of titaniumdioxide.
 7. A topical gel composition, comprising: 0.1% to 0.6% (w/w)brimonidine tartrate; 0.1% to 0.15% (w/w) methylparaben; 0.3% to 0.4%(w/w) phenoxyethanol; 0.80% to 1.50% (w/w) carbomer; 4.5% to 6.5% (w/w)propylene glycol; 4.5% to 6.5% (w/w) glycerol; 0.04% to 0.08% (w/w)water dispersible form of titanium dioxide; and purified water whereinthe pH of the topical gel composition is 5.0 to 6.5.